Balancing Treatment Efficacy and Adverse Events in Multiple Myeloma

Andrew Yee, MD

Clinical Director

Center for Multiple Myeloma

Mass General Brigham

Massachusetts General Hospital

Assistant Professor of Medicine

Harvard Medical School

Boston, MA

Targeted Oncology: What treatment options have shown the best responses and progression-free survival (PFS) for patients with myeloma?

ANDREW YEE, MD: I think the carfilzomib [Kyprolis] options tend to have the best responses and the best progression-free survival [PFS]. I remember when I first saw these data, I thought it was because CANDOR [NCT03158688] and IKEMA [NCT03275285] generally did not have lenalidomide [Revlimid]; only 40%^1,2 had lenalidomide and that is why these patients did better overall. But it turns out that in a lenalidomide-refractory cohort, this improvement continues. That may not be unexpected because for somebody who is progressing on lenalidomide, maybe changing class of therapy can be helpful. I think this fares out when you look at isatuximab-irfc [Sarclisa] and carfilzomib or daratumumab [Darzalex] and carfilzomib.

How does the adverse event (AE) profile of carfilzomib affect its clinical use?

With carfilzomib, there can be some cardiac AEs. That is accepted and patients are being admitted for heart failure. But in clinical practice, when I am using carfilzomib, I do not see that. One in 20 of my patients or 1 in 10 being admitted for heart failure. I think that has to do with when additional carfilzomib was being developed, they were pushing hydration. Now in current practice in 2024, there is not as big a push to hydrating, and also, I think the weekly dosing probably helps.

What are the considerations for treating patients with explosive disease?

If the disease is rapidly explosive, you need to have the disease [under] some semblance of control before the patient can receive the chimeric antigen receptor [CAR] T cells. That would be a great way to treat those patients because I think in a lot of these patients, that is an unmet need now that patients have rapidly explosive disease. We talk a lot about CAR T, but I think the CANDOR and chemotherapy regimens are useful tools for treating patients with myeloma. Carfilzomib is twice a week dosing. Nevertheless, with CANDOR, I think we can see improvements in PFS, and you can almost see a difference in overall survival. Then similarly, we see improvements in minimal residual disease [MRD] negativity.¹

IKEMA has a similar parallel study with a similar patient profile and again, better overall responses.² The overall responses are pretty high overall. When you start to look at more sensitive tests, you can unmask the differences in terms of depth of response and MRD negativity. When you do that, you can see the PFS from a combination of isatuximab and carfilzomib is almost 42 months. That is a pretty sizable number for this relapsed patient population.

How does carfilzomib perform across different patient subgroups, especially those refractory to lenalidomide?

The important thing across subgroups is that you see improvements in PFS. We were talking about 1q, I do not really make a distinction between the number of copies per se. This includes patients who were refractory to lenalidomide since only 40% of patients had prior lenalidomide, but those patients, even if refractory, also responded. But in terms of the stage, there is a concern for heart failure, but I think in current clinical practice using carfilzomib, I just have not seen that degree of heart failure.

How do you approach the choice between carfilzomib and pomalidomide [Pomalyst] regimens for patients with multiple myeloma?

For me, the choice of carfilzomib is a complicated discussion. I do not know if it is as controversial as a transplant question, but I think from a practical perspective, I hear the point about the pomalidomide regimen being an easier, practical regimen, because I think that for a patient with a biochemical relapse where you are telling the patient that they have relapsed disease, it is sometimes easier to change it to a general regimen like pomalidomide/dexamethasone. It is an easier regimen and an easier schedule. You are not turning the patient's life upside down. Whereas if the patient has some kind of clinical relapse, or if they just have more concerning features—if you had to do a head-to-head study, I think the carfilzomib would beat out the pomalidomide. For me, it is individualizing it to the patient's characteristics.

What are the risks if the disease is not adequately controlled early in the treatment process?

I think there is the concern that if you do not get the disease under adequate control, you could theoretically compromise the efficacy overall if you lose out the patient to subsequent therapy. If you make the wrong choice, they do not get the efficacy, and then you are not able to recover from that choice. But I think for the majority of patients, there probably is some cushion amongst the different choices.

Do you think 1 proteasome inhibitor is better than the other?

I think carfilzomib is better than bortezomib [Velcade] based on the ENDEAVOR study [NCT01568866]. At the same time, I do acknowledge that carfilzomib can be a harder drug to give in general compared with bortezomib. I do get concerned about cardiac patients, patients get shorter breath and we have to deal with that. I think there is a balanced discussion. In my sense, you have to meet the patient where the patient's disease is at.

REFERENCES:

1. Usmani SZ, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study. Lancet Oncol. 2022;23(1):65-76. doi:10.1016/S1470-2045(21)00579-9

2. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361-2371. doi:10.1016/S0140-6736(21)00592-4